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  • It should be noted that the current studies

    2022-06-22

    It should be noted that the current studies were performed in female rats. Although the oestrous cycle has been shown to modulate inflammatory processes in the periphery, data from our group has demonstrated that the phase of the oestrus cycle does not significantly alter TLR3-mediated neuroinflammatory responses [8] or fever (unpublished data). Thus, oestrous cycle is unlikely to be a significant confounding factor in the behavioural changes observed in this study. In addition, while possible sex differences in the effects of URB597 on physiological and behavioural changes cannot be ruled out, previous data has demonstrated that the acute TLR3-mediated neuroinflammatory response in the hypothalamus and the subsequent development of fever, reduced locomotor activity and body weight do not differ between male and female rats [8]. Furthermore, URB597-induced attenuation of TLR3-mediated neuroinflammatory responses in the hypothalamus was similar in male and female rats [8]. Although further studies are required, the data suggest that FAAH-mediated modulation of TLR3-induced neuroinflammation and the resultant attenuation of fever, nociceptive responding and anxiety-like behaviour may be sex-independent.
    Author’s roles
    Declaration of Interest
    Acknowledgements
    The authors would like to gratefully acknowledge funding received from the Hardiman Postgraduate Research Scholarship, The discipline of Physiology and The College of Medicine, Nursing and Health Sciences, National University of Ireland Galway. The funding sources had no input into the study design, collection, analysis and interpretation of the data or writing of the manuscript.
    In recent years, there has been an increasing interest in the therapeutic potential of boron-containing compounds as enzyme inhibitors, boron neutron capture therapy (BNCT) agents, and drug delivery devices. For example, bortezomib, a dipeptidyl boronic 360A approved in 2003 by the FDA for the treatment of multiple myeloma (MM) and mantle cell lymphoma, stands out as one of the most potent proteasome inhibitors so far available. Boronic acids inhibit hydrolytic enzymes such as serine proteases, through the formation of a tetracoordinate–boronate complex by coordination of the catalytic serine residue, 360A thus acting as transition-state analogs., In 2008, Minkkilä et al. reported that a series of commercially available phenyl-, heteroaryl-, alkyl-, and alkenylboronic acids behaved as potent and selective fatty acid amide hydrolase (FAAH) inhibitors and, at the same time, some boronic acid derivatives were patented as reversible FAAH inhibitors by Infinity Pharmaceuticals. FAAH is a member of the amidase signature family of serine hydrolases that cleaves and regulates a broad range of endogenous signaling lipid amides, such as the prototypical endocannabinoid anandamide (AEA), the anti-inflammatory substance palmitoylethanolamide (PEA), the sleep-inducing agent oleamide (OA), and the analgesic and satiety regulating mediator oleoylethanolamide (OEA). Thus, blockade of FAAH represents a promising approach for the treatment of various disease states such as pain, inflammatory, and neuropsychiatric disorders, and, toward this ends, many classes of FAAH inhibitors, including α-ketoheterocycles, carbamates, and ureas, have been reported. Although in animal models FAAH inhibitors have proved to be effective analgesic agents, devoid of the CNS side effects that arise when a cannabinoid receptors agonist is used, data on their clinical efficacy are less encouraging. For example, the potent and selective FAAH inhibitor PF-04457845, evaluated as an analgesic in randomized, placebo-controlled phase II clinical trials, was apparently ineffective. Among the reasons for this failure, the fact that FAAH inhibition might indirectly lead to activation of other, non-cannabinoid receptors involved in nociception, such as transient receptor potential vanilloid 1 (TRPV1) channel, should be taken into account. TRPV1, a non-selective cation channel belonging to the large family of transient receptor potential (TRP) ion channels, is activated by a variety of stimuli, including noxious heat, protons, endogenous substances such as AEA, OEA, and lipoxygenase products, and exogenous compounds such as capsaicin (), and has emerged as a promising therapeutic target for pain management.